Crystalline bis[(e)-7-[4-(4-fluorophenyl)-6-isopropyl-2-[methyl(methylsulfonyl)amino]pyrimidin-5-yl](3R,5S)-3,5-dihydroxyhept-6-enoic acid]calcium salt

ABSTRACT

The present invention relates to a crystalline form of the compound bis[(E)-7-[4-(4-fluorophenyl)-6-isopropyl-2-[methyl(methylsulfonyl)amino]pyrimidin-5-yl](3R,5S)-3,5-dihydroxyhept-6-enoic acid]calcium salt, as well as processes for its manufacture and pharmaceutical compositions comprising the crystalline form, which is useful as an agent for treating hyperlipidemia, hypercholesterolemia and atherosclerosis.

This application is the National Phase of International ApplicationPCT/GB99/04439 filed Dec. 23, 1999 which designated the U.S. and thatInternational Application was published under PCT Article 21(2) inEnglish.

The present invention relates to a novel crystalline chemical compoundand more particularly to a novel crystalline form ofbis[(E)-7-[4-(4-fluorophenyl)-6-isopropyl-2-[methyl(methylsulfonyl)amino]pyrimidin-5-yl](3R,5S)-3,5-dihydroxyhept-6-enoicacid]calcium salt, hereinafter referred to as “the Agent”, andillustrated in Formula I hereinafter, which compound is an inhibitor ofthe enzyme 3-hydroxy-3-methylglutaryl-coenzyme A reductase (HMG CoAreductase) and is useful as a pharmaceutical agent, for example in thetreatment of hyperlipidemia, hypercholesterolemia and atherosclerosis,as well as other diseases or conditions in which HMG CoA reductase isimplicated. The invention also relates to processes for the manufactureof the crystalline form, pharmaceutical compositions comprising thecrystalline form and the use of the crystalline form in medicaltreatment.

European Patent Application, Publication No. 521471 (hereinafter EPA521471), which is herein incorporated by reference, discloses anamorphous (powder) form of the Agent, prepared by dissolving thecorresponding sodium salt in water, adding calcium chloride andcollecting the resultant precipitate by filtration.

An amorphous form of a compound intended for pharmaceutical use may giverise to manufacturing problems and there is a need to identifycrystalline forms of such compounds which have different physicalcharacteristics compared to the amorphous form which may assist in themanufacture of the compound, or formulation of the compound, to thepurity levels and uniformity required for regulatory approval.Crystalline forms of such compounds may also possess improvedpharmacological characteristics, for example, improved bioavailability.

We have now surprisingly and unexpectedly discovered that the Agent canbe prepared in a crystalline form.

According to the present invention there is provided a crystalline formof the Agent and hydrates thereof having an X-ray powder diffractionpattern with specific peaks at 2-theta=4.92, 11.50, 6.93, 9.35, 23.12and 18.76° (hereinafter referred to as Form A).

The X-ray powder diffraction spectra was determined by mounting a sampleof the crystalline form on Siemans single silicon crystal (SSC) wafermounts and spreading out the sample into a thin layer with the aid of amicroscope slide. The sample was spun at 30 revolutions per minute (toimprove counting statistics) and irradiated with X-rays generated by acopper long-fine focus tube operated at 40 kV and 40 mA with awavelength of 1.5406 angstroms. The collimated x-ray source was passedthrough an automatic variable divergence slit set at V20 (20 mm pathlength) and the reflected radiation directed through a 2 mm antiscatterslit and a 0.2 mm detector slit. The sample was exposed for 4 secondsper 0.02 degree 2-theta increment (continuous scan mode) over the range2 degrees to 40 degrees 2-theta in theta-theta mode. The running timewas 2 hours 6 minutes and 40 seconds. The instrument was equipped with ascintillation counter as detector. Control and data capture was by meansof a DECpc LPv 433sx personal computer running with Diffrac AT (Socabim)software.

The X-ray powder diffraction spectra of a typical sample of Form A isshown in FIG. 1 hereinafter. It will be understood that the 2-thetavalues of the X-ray powder diffraction pattern may vary slightly fromone machine to another or from one sample of Form A to another, and sothe values quoted are not to be construed as absolute.

Typically Form A is obtained in a hydrated form with, for example, awater content of about 7% w/w.

A further aspect of the present invention comprises a process for thepreparation of Form A wherein Form A is caused to crystallise from amixture of the Agent, water and one or more organic solvents. Theoptimum ratio of organic solvents and water in the mixture to obtainForm A is dependent on the characteristics of the organic solvents usedand the process conditions employed. The precise conditions may beempirically determined. For example, Form A may be obtained bysuspending the amorphous form of the Agent in water containing aco-solvent, such as acetonitrile, acetone or a mixture of methanol andmethyl tert-butyl ether (MTBE), warming the mixture to obtain completesolution and then allowing the solution to cool, followed by isolationof Form A, such as by filtration. Suitable mixtures of water andco-solvent include, for example, 1:1 water/acetonitrile, 1:1water/acetone and 1:1:1 water/methanol/MTBE, the ratios given being byvolume. The amorphous form of the Agent to be used as starting materialfor the manufacture of Form A may be obtained, for example, as describedin EPA 521471.

The utility of the compound of the invention may be demonstrated bystandard tests and clinical studies, including those described in EPA521471.

According to a further feature of the invention is a method of treatinga disease condition wherein inhibition of HMG CoA reductase isbeneficial which comprises administering to a warm-blooded mammal aneffective amount of the Agent. The invention also relates to the use ofForm A in the manufacture of a medicament for use in a diseasecondition.

The compound of the invention may be administered to a warm-bloodedanimal, particularly a human, in need thereof for treatment of a diseasein which HMG CoA reductase is implicated, in the form of a conventionalpharmaceutical composition. Therefore in another aspect of theinvention, there is provided a pharmaceutical composition comprisingForm A in admixture with a pharmaceutically acceptable carrier.

Such compositions may be administered in standard manner for the diseasecondition that it is desired to treat, for example by oral, topical,parenteral, buccal, nasal, vaginal or rectal administration or byinhalation. For these purposes the Agent may be formulated by meansknown in the art into the form of, for example, tablets, capsules,aqueous or oily solutions, suspensions, emulsions, creams, ointments,gels, nasal sprays, suppositories, finely divided powders or aerosolsfor inhalation, and for parenteral use (including intravenous,intramuscular or infusion) sterile aqueous or oily solution orsuspensions or sterile emulsions. A preferred route of administration isoral. The Agent will be administered to humans at a daily dose in, forexample, the ranges set out in EPA 521471. The daily doses may be givenin divided doses as necessary, the precise amount of the Agent receivedand the route of administration depending on the weight, age and sex ofthe patient being treated and on the particular disease condition beingtreated according to principles known in the art.

According to a further feature of the invention, there is provided aprocess for the manufacture of a pharmaceutical composition containingForm A as active ingredient, which comprises admixing Form A togetherwith a pharmaceutically acceptable carrier.

The invention will now be illustrated by the following non-limitingExample.

EXAMPLE 1

Amorphous form of the Agent (465 mg) was added to a mixture of water (5ml) and acetonitrile (5 ml) at 15° C. The mixture was warmed to 40° C.to obtain complete solution. The mixture was then cooled slowly toambient temperature and stirred for 16 hours. The crystalline productwas separated by filtration at ambient temperature and dried at 50°under vacuum to give Form A (337 mg) as white crystals.

X-ray powder diffraction (XRD):

Peak Relative Intensity Number 2θ d-Spacing Counts/sec (>20%) 1 4.9217.945 820.25 100 2 11.50 7.686 258.75 31.55 3 6.93 12.750 230.25 28.074 9.35 9.455 213.75 26.06 5 23.12 3.843 212.75 25.94 6 18.76 4.726 177.521.64

Water content 7.1% w/w

¹NMR (d⁶-DMSO) δ: 7.7 (2H, t), 7.3 (2H, t), 6.5 (1H, d), 5.5 (1H,dd),4.2 (1H, m), 3.8 (1H, m), 3.5 (3H, s), 1.9-2.1 (2H, dd), 1.3-1.5 (2H,m), 1.2 (6H, d)

Mass Spectrum: MH+482.3

What is claimed is:
 1. A crystalline form of the compoundbis[(E)-7-[4-(4-fluorophenyl)-6-isopropyl-2-[methyl(methylsulfonyl)amino]pyrimidin-5-yl](3R,5S)-3,5-dihydroxyhept-6-enoicacid]calcium salt of the formula I

in hydrated form having an X-ray powder diffraction pattern withspecific peaks at 2-theta (2θ)=4.92, 11.50, 6.93, 9.35, 23.12 and18.76°.
 2. A pharmaceutical composition comprising the crystalline formof compound as claimed in claim 1, together with a pharmaceuticallyacceptable carrier.